Defining the Regulation of GD2 Expression to Enhance Immunotherapy for Neuroblastoma
Abstract
This proposal addresses the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of neuroblastoma and pediatric, adolescent, and young adult cancers and the FY21 PRCRP Military Health Focus Area of Mission Readiness. Neuroblastoma is the most common solid tumor occurring outside the brain in children and accounts for nearly 10% of pediatric cancer deaths. Approximately half of children diagnosed with neuroblastoma have high-risk disease, which requires years of highly toxic therapy that causes many debilitating side effects and only cures approximately 60% of patients. Survivors of neuroblastoma often suffer from hearing loss, heart problems, and stunted growth. Approximately 6 years ago, the Food and Drug Administration approved a new immunotherapy to treat neuroblastoma. This antibody recognizes a sugar expressed on the surface of neuroblastoma cells called GD2. The use of this antibody has improved the survival rate of children with high-risk neuroblastoma, but approximately 40% of patients will still relapse and eventually die of their disease. Researchers have been unsure why some tumors can escape this anti-GD2 antibody. We have discovered that neuroblastoma tumors are capable of losing or reducing expression of GD2 so that anti-GD2 antibody is no longer effective. This research project will allow us to understand how neuroblastoma tumors lose GD2. This biologic understanding will then help us to develop two new therapies for children with neuroblastoma to overcome GD2 loss. First, we will test already approved drugs to reverse GD2 loss, re-establishing the efficacy of anti-GD2 antibody. Second, our studies have revealed that neuroblastoma tumors have an Achilles’ heel – when they lose GD2, they gain other targets. We will test new antibodies against those targets. Both of these approaches have the potential to dramatically improve the treatment outcomes for children with high-risk neuroblastoma. By the conclusion of this grant period (within 4 years), we plan to translate at least one of these two new approaches to a clinical trial. This proposal will address the FY21 PRCRP overarching challenge to transform cancer treatment through the identification of…new targets, especially for advanced disease…; improve immunotherapy; and eliminate the risks of therapy-associated toxicity. This is highly relevant to active-duty Service Members and their children. Neuroblastoma is one of the most common types of pediatric cancers, and a Service Member whose child is suffering from this disease will, most likely, be called home from deployment. By generating new therapeutics for these patients, we will reduce the gap in treatment that negatively affects their children and we will enable their return to duty.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210624
Entities
People
- Robbie G Majzner
Organizations
- Stanford University
- United States Army